Patent EA-001577-B1 (EA)
Title: 7alpha-(ξ-AMINOALKYL)ESTRATRIENES, PROCESS FOR PREPARING THE SAME, PHARMACEUTICAL PREPARATIONS CONTAINING SAID 7alpha-(ξ-AMINOALKYL)ESTRATRIENES AND THEIR USE FOR PREPARING MEDICAMENTS
Inventor: BOLHMANN ROLF
IPC: C07J53/00
Filed: 1997-08-20
Abstract: 1. Substituted 7α-(ξ-aminoalkyl)estratrienes of general formula I   in which side chain SK is a radical of partial formula   whereby m is 4, 5 or 6, n is 0, 1 or 2, x is 0, 1 or 2, A is a hydrogen atom or a C1-C5 alkyl group, B and D each are a hydrogen atom, or A and B together are an alkylene group -(CH2)p- wherein p=2, 3, 4 or 5, and D is a hydrogen atom or A and D together are an alkylene group -(CH2)q- wherein q=2, 3 or 4, and B is a hydrogen atom, and E is an unsubstituted ethyl radical or an ethyl radical that is fluorinated in one to five places, or terminal substituent -(CH2)3-E in the side chain is replaced by an optionally substituted aryl or heteroaryl radical, which is bonded directly or via a mono-, di- or trimethylene group to the sulfur atom, R<3> is a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of formula R<3>'-C(O)-, in which R<3>' is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical, R<11> is a hydrogen atom, a halogen atom or a nitrooxy group -O-NO2, R<14>, R<15α>, R<15β>, R<16α> and R<16β> each are a hydrogen atom or R<14> and R<15α> are an additional bond or a methylene bridge, or R<15β> is a methyl group and R<15α> is a hydrogen atom, or R<15α> and R<15β> in each case are a methyl group, or R<15β> and R<16β> together are a methylene bridge, or R<16α> or R<16β> is a halogen atom or R<16α> and R<16β> together are a methylidene group and the remaining substituents R<14>, R<15α>, R<15β>, R<16α> and R<16β> are each a hydrogen atom, R<17>' in α- or β-position is a hydrogen atom, a C1-C5 alkyl, C2-C5 alkenyl or C2-C5 alkinyl group or a trifluoromethyl group and R<17>'' is a hydrogen atom or a radical of partial formula R<17>''' -C(O)-, in which R<17>''' is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms, or, if R<17>' is in α- position, R<17>' together with R<14> means an ethano bridge, provided that if A and B together are not -(CH2)p- or A and D together are not -(CH2)q-, at least one of substituents R<11>, R<14>, R<15α>, R<15β>, R<16α> and R<16β> is not a hydrogen atom, as well as their physiologically compatible addition salts with organic and inorganic acids. 2. Estratrienes according to Claim 1, in which m is 5. 3. Estratrienes according to Claim 1, in which n is 0. 4. Estratrienes according to Claim 1, in which n is 1. 5. Estratrienes according to Claim 1, in which n is 2. 6. Estratrienes according to Claim 1, in which A is a methyl group. 7. Estratrienes according to Claim 1, in which x is 0. 8. Estratrienes according to Claim 1, in which x is 1. 9. Estratrienes according to Claim 1, in which x is 2. 10. Estratrienes according to Claim 6, in which n is 1. 11. Estratrienes according to Claim 1, in which A and B together are -(CH2)3-. 12. Estratrienes according to Claim 11, in which n is 0. 13. Estratrienes according to Claim 12, in which x is 0. 14. Estratrienes according to Claim 1, in which E is a perfluoroethyl radical. 15. Estratrienes according to Claim 1, in which R<3> is a hydrogen atom. 16. Estratrienes according to Claim 1, in which R<3> is a methyl group. 17. Estratrienes according to Claim 1, in which R<3> is an acetyl group. 18. Estratrienes according to Claim 1, in which R<11> is a hydrogen atom. 19. Estratrienes according to Claim 1, in which R<11> is a fluorine atom. 20. Estratrienes according to Claim 1, in which R<11> is a nitrooxy group. 21. Estratrienes according to Claim 1, in which R<14> is a hydrogen atom. 22. Estratrienes according to Claim 1, in which R<14> together with R<15α> forms an additional bond. 23. Estratrienes according to Claim 1, in which R<15β> is a methyl group. 24. Estratrienes according to Claim 1, in which R<15β> and R<16β> together form a methylene bridge. 25. Estratrienes according to Claim 1, in which R<16α> is a halogen atom (F, Cl, Br, I). 26. Estratrienes according to Claim 25, in which R<16α> is a fluorine atom. 27. Estratrienes according to Claim 1, in which R<16α> and R<16β> together form a methylidene group. 28. Estratrienes according to Claim 1, in which R<17> is in α-position. 29. Estratrienes according to Claim 28, in which R<17> is a trifluoromethyl group. 30. Estratrienes according to Claim 28, in which R<17> is a methyl group. 31. Estratrienes according to Claim 28, in which R<17> is a hydrogen atom. 32. Estratrienes according to Claim 1, in which R<17> is in β-position. 33. Estratrienes according to Claim 32, in which R<17> is a methyl group. 34. Estratrienes according to Claim 32, in which R<17> is a hydrogen atom. 35. Estratrienes according to Claim 28, in which R<14> and R<17> together form an ethano bridge. 36. Estratrienes according to Claim 1, in which SK is a radical of partial formula with x=0, 1 or 2.   37. Estratrienes according to Claim 13, in which m=5, E is a perfluoroethyl radical and the conformation of the 2-carbon atom of the heterocycle is R. 38. Estratrienes according to Claim 13, in which m=5, E is a perfluoroethyl radical and the conformation of the 2-carbon atom of the heterocycle is S. 39. Estratrienes according to Claim 37, in which R<17> is in α-position and is a hydrogen atom. 40. Estratrienes according to Claim 1, namely 14,17-ethano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 14,17-ethano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 3,17β-diacetoxy-14α,17α-ethano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene, 14,17-ethano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 17α-trifluoromethyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β,16β-methano-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β,16β-methano-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β,16β-methano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β,16β-methano-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 15β,17α-dimethyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-17β-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17α-diol, 16α-fluoro-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-17α-methyl-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10)-triene-3,17α-diol, 16α-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 16α-fluoro-7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentylthio)propylamino]pentyl}estra-1,3,5(10),14-tetraene-3,17β-diol, 7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfinyl)propylamino]pentyl}estra-1,3,5(10),14-tetraene-3,17β-diol, 7α-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentanesulfonyl)propylamino]pentyl}estra-1,3,5(10),14-tetraene-3,17β-diol, 7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 7α-{5-[(2R)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 17α-methyl-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-7α-{5-[2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentylthiomethyl)pyrrolidin-l-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfinylmethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 11β-fluoro-17α-methyl-7α-{5-[(2S)-2-(4,4,5,5,5-pentafluoropentanesulfonylmethyl)pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17β-diol, 7 α-{5-[(2S)-2-(4,4,5,5,5-p